Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year re-search project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer's disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of

The Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has provided clinical, operational and data management support to ADNI since its inception. This paper reviews the activities and accomplishments of the core in support of ADNI aims. These include the enrollment and follow-up of over 800 subjects in the three original cohorts: healthy controls, amnestic MCI (now referred to as late MCI, or LMCI) and mild Alzheimer's disease (AD) in the first phase of ADNI (ADNI 1), with baseline longitudinal clinical and cognitive assessments. These data, when combined with genetic, neuroimaging and cerebrospinal fluid measures, have provided important insights into the neurobiology of the AD spectrum. Further, these data have facilitated the development of novel clinical trial designs. ADNI has recently been extended with funding from an NIH Grand Opportunities (GO) award, and the new ADNI GO phase has been launched; this includes the enrollment of a new cohort, called early MCI (EMCI), with milder episodic memory impairment than the LMCI group. An application for a further 5 years of ADNI funding (ADNI 2) was recently submitted. This funding would support ongoing follow-up of the original ADNI 1 and ADNI GO cohorts, as well as additional recruitment into all categories. The resulting data would provide valuable data on the earliest stages of AD, and support the development of interventions in these critically important populations.

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.

Calcitonin gene-related peptide (CGRP) is a ubiquitous neuropeptide found at the very centers of the migraine process, both centrally and peripherally. It has been under careful study for approximately 25 years. Several CGRP-receptor antagonists are being evaluated for acute treatment of episodic migraine. Three monoclonal antibodies are being studied for prevention of episodic migraine, and 1 monoclonal antibody is being studied for prevention of chronic migraine. In this review, we discuss the role of CGRP in normal physiology and the consequences of CGRP inhibition for human homeostasis. We then review the current state of development for CGRP-receptor antagonists and CGRP monoclonal antibodies. We close by speculating on the potential clinical role of CGRP antagonism in the acute and preventive treatment of episodic and chronic migraine.Key words: calcitonin gene-related peptide, antibodies, migraine, chronic migraine (Headache 2013;53:1230-1244 Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide that is derived from the gene encoding calcitonin by alternative splicing of mRNA and proteolytic processing of its precursor. 1,2Despite their common origin, calcitonin and CGRP are involved in totally different physiological processes in humans. While calcitonin is mainly related to calcium homeostasis and bone remodeling, CGRP is involved in vasodilation and sensory transmission.CGRP is found in literally every organ system in the body, 3 occurring in 2 isoforms, a-and b-CGRP. 4,5a-CGRP is the predominant form in the peripheral nervous system, while the b-isoform is mainly present in the enteric nervous system. 6 CGRP is highly conserved across species, 7 suggesting that the neuropeptide is of importance in functions that were established relatively early in mammalian evolution.Immunohistochemistry demonstrated that CGRP is mainly produced in the cell bodies of both ventral and dorsal root neurons.8 Radioimmunology further demonstrated that this molecule is especially common in the trigeminal system, where up to 50% of the neurons produce it.9 Indeed, the potential role of CGRP in migraine pathophysiology was suggested more than 20 years ago, 10,11 and since then, our knowledge of the peptide and its role in the pathophysiology of migraine has increased substantially and has

Ischemia-reperfusion (I/R) is an important cause of acute renal failure (ARF). The complement system appears to be essentially involved in I/R injury. However, via which pathway the complement system is activated and in particular whether the mannose-binding lectin (MBL)-pathway is activated is unclear. This tempted us to study the activation and regulation of the MBL-pathway in the course of experimental renal I/R injury and in clinical post-transplant ARF. Mice subjected to renal I/R displayed evident renal MBL-depositions, depending on the duration of warm ischemia, in the early reperfusion phase. Renal deposition of C3, C6 and C9 was observed in the later reperfusion phase. The deposition of MBL-A and -C completely co-localized with the late complement factor C6, showing that MBL is involved in complement activation in the course of renal I/R injury. Moreover, the degree of early MBL-deposition correlated with complement activation, neutrophil-influx, and organ-failure observed in the later reperfusion phase. In serum of mice subjected to renal I/R MBL-A, levels increased in contrast to MBL-C levels, which dropped evidently. In line, liver mRNA levels for MBL-A increased, whereas MBL-C levels decreased. Renal MBL mRNA levels rapidly dropped in the course of renal I/R. Finally, in human biopsies, MBL-depositions were observed early after transplantation of ischemically injured kidneys. In line with our experimental data, in ischemically injured grafts displaying post-transplant organ-failure extensive MBL depositions were observed in peritubular capillaries and tubular epithelial cells. In conclusion, in experimental renal I/R injury and clinical post-transplant ARF the MBL-pathway is activated, followed by activation of the complement system. These data indicate that the MBL-pathway is involved in ischemia-induced complement activation.

CGRP is an extensively studied neuropeptide that has been implicated in the pathophysiology of migraine. While a number of small molecule antagonists against the CGRP receptor have demonstrated that targeting this pathway is a valid and effective way of treating migraine, off‐target hepatoxicity and formulation issues have hampered the development for regulatory approval of any therapeutic in this class. The development of monoclonal antibodies to CGRP or its receptor as therapeutic agents has allowed this pathway to be re‐investigated. Herein we review why CGRP is an ideal target for the prevention of migraine and describe four monoclonal antibodies against either CGRP or its receptor that are in clinical development for the treatment of both episodic and chronic migraine. We describe what has been publically disclosed about their clinical trials and future clinical development plans.